Histone Deacetylase Inhibitors Up-Regulate the Expression of Tight Junction Proteins
Open accessAbstract
Histone deacetylase (HDAC) inhibitors promote cell maturation, differentiation, and apoptosis through changes in gene expression. Differentiated epithelial cells are characterized by apical tight junctions (TJ), which play a role in cell-cell adhesion, polarity, and the permeability barrier function of epithelia. The relationship between cellular differentiation and expression of TJ-associated proteins is not known. Here, we investigated whether HDAC inhibitors affect the expression of TJ proteins in cultured cells by immunoblotting, immunofluorescence, and quantitative real-time, reverse transcription-PCR. We find that the HDAC inhibitor sodium butyrate significantly up-regulates the protein levels of cingulin, ZO-1, and ZO-2 in Rat-1 fibroblasts, cingulin in COS-7 cells, and cingulin and occludin in HeLa cells. Levels of mRNA for cingulin, ZO-1, and ZO-2 are also increased in sodium butyrate–treated Rat-1 fibroblasts. Up-regulation of cingulin is reversible and dose dependent and requires de novo protein synthesis and protein kinase activity, because it is inhibited by cycloheximide and by the protein kinase inhibitor H-7. Up-regulation of TJ proteins by sodium butyrate is linked to the ability of sodium butyrate to inhibit HDAC activity, because suberoylanilide hydroxamic acid, a HDAC inhibitor of a different structural class, also up-regulates cingulin, ZO-1, and ZO-2 expression in Rat-1 fibroblasts. These results indicate that cellular differentiation correlates with kinase-dependent up-regulation of the expression of specific TJ proteins.
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Cingulin is a tight junction protein whose decreased levels have been associated with gut barrier dysfunction leading to increased inflammation.
“Cingulin is a tight junction protein whose decreased levels have been associated with gut barrier dysfunction leading to increased inflammation50.”
From Gut Dysbiosis Is Linked to Hypertension (2015) · cites this paper as [50]
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References 61 · Cited by 168
- Authors
- Bordin, M., D'Atri, F., Guillemot, L., & Citi, S.
- Affiliations
- University of Geneva (CH)
- 1Department of Molecular Biology, University of Geneva, Geneva, Switzerland and
- Venue
- Molecular Cancer Research
- Published
- 2004-12-01
- Volume
- 2
- Issue
- 12
- Pages
- 692-701
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- OpenAlex
- W2305690510
- Cited by
- 168
- References
- 61
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 11 · 2021: 11 · 2020: 13 · 2019: 9 · 2018: 12 · 2017: 12 · 2016: 14 · 2015: 6 · 2014: 6 · 2013: 5 · 2012: 6
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, other-oa)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- histone deacetylase inhibitors, tight junction proteins, sodium butyrate, cingulin, ZO-1, ZO-2, occludin, epithelial differentiation, protein kinase activity, vorinostat, gene expression regulation, cell-cell adhesion
- MeSH terms
- Vorinostat, Animals, Butyrates, Cell Adhesion, Cell Differentiation, Cycloheximide, Dose-Response Relationship, Drug, Enzyme Inhibitors, Fibroblasts, HeLa Cells, Humans, Hydroxamic Acids, Membrane Proteins, Microfilament Proteins, Microscopy, Fluorescence, Immunoblotting, Up-Regulation, 3T3 Cells, Tight Junctions, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, COS Cells, Reverse Transcriptase Polymerase Chain Reaction, Protein Kinase Inhibitors, Mice, Rats, Histone Deacetylase Inhibitors, Isobutyrates
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